This proposal, to conduct a multi-center, case-cohort study in very low birthweight (VLBW) infants, is designed to identify the antecedents of disorders of developing white matter, disorders which now can be identified in the neonatal period by bedside cranial ultrasonography (US), a non-invasive procedure. Recent studies in VLBW infants have shown that the US findings of parenchymal echodensities and lucencies (PEL) of the white matter predict later handicap better than do the more commonly studied lesions, germinal matrix and intraventricular hemorrhage (IVH). Infants weighing 1500 grams or less at five participating units will be studied by US on days 1-2, 5-7, and 21-23 during a 36-month enrollment period. Cases will be the approximately 330 infants with PEL, and the subcohort of noncases will begin with 693 lesion-free babies selected from among a surveyed population of more than 2160 infants. To elucidate the natural history of PEL, cases will have a late US scan at 60 days. The large number of cases will allow a detailed analysis of the typology of white matter lesions. A single center will perform detailed neuropathologic examinations, focusing especially on US-pathology correlation. The central objective of the study is to identify risk factors for PEL and its subtypes by comparing cases to noncases on a range of antecedent variables obtained by maternal interview, medical record abstraction, and systematic placental pathology and microbiology. Major hypothesized risk factors include maternal endocrine and reproductive disorders, smoking, placental funisitis or amnionitis, intrapartum fetal acidosis, neonatal hypotension and ventilatory problems, and ipsilateral IVH. The dominant mechanisms suspected are ischemia, infarction and/or infection. By identifying the risk factors for PEL, currently the best morphologic predictor of later cerebral palsy, this study is expected to contribute to the prevention of motor handicaps in children born prematurely.